The invention relates to novel antitussive/antihistiminic/decongestant tannate compositions. The compositions contain as essential ingredients carbetapentane tannate, pyrilamine tannate and phenylephrine tannate.
A considerable number of tannic acids occur in nature. Chemically, these acids are described as polymers of different hydroxybenzoic acids. Generally, when the term tannic acid is employed, as in the present case, the acid referred to is gallotannic acid, the internal ester of gallic acid also frequently referred to as tannin.
Tannic Acid consists of an amorphous powder glistening scales or spongy masses varying in color from yellowish-white to light brown. Tannic acid is very soluble in water, glycerine or alcohol.
Tannic acids are usually obtained from glycosides which consist of several molecules of a tannic acid in combination with glucose.
Commercially available, tannic acid, also known as Tannin, has a complex non-uniform chemistry, usually contains from about 5% to about 10% by weight water, has a molecular weight of about 1700, and is typically produced from Turkish or Chinese nutgall.
Carbetapentane, known chemically as 2-[2-(diethylamino)ethoxy]ethyl 1-phenylcyclopentanecarboxylate is an antitussive compound that is described in U.S. Pat. No. 2,842,585 and is structurally related to caramiphen. Carbetapentane citrate has a melting point of 93xc2x0 C. and occurs as a white powder freely soluble in water and slightly soluble in alcohol.
Carbetapentane has an atropine-like action that depresses the cough reflex by selective central nervous system depression.
Pyrilamine is one of the oldest and most enduring antihistaminic drugs, known chemically as N-[(4-methoxyphenyl)methyl]-Nxe2x80x2,Nxe2x80x2-dimethyl-N-2-pyridinyl-1,2-ethanediamine, its preparation is disclosed in U.S. Pat. No. 2,502,151 and is an oily liquid. Pyrilamine hydrochloride salt is very soluble in water and has a melting point of 143-143.5xc2x0 C. whereas the maleate salt is slightly soluble in water, benzene and ether and has a melting point of 100-101xc2x0 C.
Phenylephrine, known chemically as (xe2x88x92)-m-hydroxy-xcex1-[(methylamino)-methyl] benzyl alcohol, is a synthetic, optically active sympathomimetic amine which has one hydroxyl group on the benzene ring. The hydroxyl group is placed in the position meta to the aliphatic side chain. The meta position affords optimal activity and phenylephrine (neo-synephrine) replaced an older preparation, synephrine, in which the hydroxyl was in the para position.
Phenylephrine hydrochloride is available in the form of the levorotatory isomer, a white, odorless, non-hygroscopic, crystalline compound possessing a bitter taste. Phenylephrine hydrochloride has a melting point of 140-145xc2x0 C. and is freely soluble in water and alcohol.
Antitussive, antihistamine and decongestant compounds in the form of their free bases as well as their salts, e.g. hydrochloride, citrate, maleate, tannate, etc., are well known. Antitussives, antihistamines and decongestants in the form of their tannate salts are very desirable because such salts are generally stable and may be combined in such form without any untoward side effects.
Antitussives, antihistamines and decongestants in the form of their tannate salts are typically prepared by reacting the free base, e.g. carbetapentane, pyrilamine, phenylephrine, etc. with tannic acid in the presence of a volatile solvent, usually isopropanol. Typically, in the conventional isopropanol route, the antitussive, antihistaminic or decongestant free base and the tannic acid will be present in the isopropanol at a concentration of about 20% based on the weight of the reaction mixture. The reaction mixture is stirred for about one hour while maintaining the mixture at 60-70xc2x0 C. The reaction mixture is cooled to room temperature and then filtered, washed with isopropanol and then vacuum dried. Alternative routes to the tannate salts are described in U.S. Pat. No. 5,599,846 and U.S. Pat. No. 5,663,415.
It has now been found that the novel combination of carbetapentane tannate, pyrilamine tannate and phenylephrine tannate produces a composition having antitussive, antihistaminic and sympathomimetic decongestant properties superior to the use of any one of the tannate compounds alone.
The compositions of the present invention may be prepared for oral administration in the form of powders, capsules, elixirs, syrups and the preferred forms of tablets or suspensions formulated so that ideally each tablet contains approximately 50 to 75 mg of carbetapentane tannate, preferably about 60 mg of carbetapentane tannate, approximately 30 to 50 mg pyrilamine tannate, preferably about 40 mg of pyrilamine tannate, and approximately 5 to 15 mg phenylephrine tannate, preferably about 10 mg phenylephrine tannate or that ideally each 5 mL (approximately 1 teaspoon) of suspension would contain approximately 20 to 30 mg carbetapentane tannate, preferably 30 mg of carbetapentane tannate, 25 to 30 mg pyrilamine tannate, preferably 30 mg of pyrilamine tannate, and 3 to 8 mg of phenylephrine tannate, preferably 5 mg of phenylephrine tannate.
Tablets containing the unique tannate combination of the present invention are prepared in a conventional manner by the addition of suitable pharmaceutical carriers including fillers, diluents, colorants, lubricants and the like as well as conventional and well known binding and disintegrating agents. A typical tablet composition of the present invention containing starch, dibasic calcium phosphate, colorants, magnesium stearate, methylcellulose, polygalacturoic acid, povidone and talc as described in Example 1 which follows is prepared by well known conventional tabletting techniques such as those disclosed in U.S. Pat. Nos. 3,018,221; 2,798,024 and 2,757,124.